JP2005206603A - Preparation of candesartan cilexetil - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for preparation of candesartan cilexetil. <P>SOLUTION: A process for the synthesis of cilexetil trityl candesartan from a reaction of trityl candesartan with cilexetil halide in the presence of a base and a low boiling organic solvent, optionally, the reaction may be conducted in the presence of a phase transfer catalyst. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

Related Applications This application is filed with US Provisional Patent Application No. 60 / 512,566 (filed on Oct. 16, 2003); 60 / 523,524 (filed on Nov. 18, 2003); 60 / 537,995 (January 21, 2004) Claims the benefit of 60 / 568,649 (filed on May 5, 2004).

The present invention encompasses the preparation of candesartan trityl cilexetil. The present invention also includes the preparation of candesartan cilexetil by deprotecting cilexetil trityl candesartan (TCC) using at least one organic solvent and / or at least one organic acid. The present invention includes crystallizing and recrystallizing candesartan cilexetil.

BACKGROUND OF THE INVENTION Candesartan is a potent long-acting selective AT ₁ subtype angiotensin II receptor antagonist. Candesartan satisfies the high titer requirements, but is difficult to be absorbed into the body when administered orally. To overcome this poor absorption, a prodrug, candesartan cilexetil, was developed. During absorption in the gastrointestinal tract, candesartan cilexetil is rapidly and completely hydrolyzed to candesartan. The chemical name for candesartan is 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylic acid. The chemical name of candesartan cilexetil is (±) -1-[[(cyclohexyloxy) carbonyl] oxy] ethyl-2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) 1,1 '-Biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate. Candesartan cilexetil is a white to off-white powder that is only slightly soluble in water and methanol. Candesartan cilexetil has an asymmetric center in the ester portion of the molecule, but candesartan cilexetil is sold as a racemic mixture.

Angiotensin II is produced by a reaction catalyzed by angiotensin I (ACE, kinase II) from angiotensin I. Angiotensin II is a major vasopressor in the renin-angiotensin system, which has effects including vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal reabsorption of sodium. Angiotensin II helps keep blood pressure constant despite hydration, sodium intake, and other physiological changes. Angiotensin II also acts as a regulator, such as inhibition of sodium excretion by the kidney, inhibiting norephedrine reuptake and stimulating aldosterone biosynthesis. Candesartan blocks vasoconstriction and angiotensin II aldosterone secretion by selectively blocking the binding of angiotensin II to the AT ₁ receptor in many tissues (eg, vascular smooth muscle and adrenal glands). Candesartan By inhibiting angiotensin II binding to AT ₁ receptors, interferes vasoconstriction by AT ₁ receptors. Inhibiting vasoconstriction with angiotensin II has been found useful in hypertensive patients. The United States Food and Drug Administration has approved candesartan alone or in combination with other antihypertensive agents for the treatment of hypertension.

US Patent No. 5,196,444 discloses Example 7 and 1-[[(cyclohexyloxy) carbonyl] oxy] ethyl-2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) 1,1 'Biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate is converted to 2-ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl) biphenyl-4 in DMF -Ile] methyl] benzimidazole-7-carboxylic acid was reacted with cyclohexyl-1-iodoethyl carbonate to produce cilexetil trityl candesartan and deprotected with methanolic hydrochloric acid to produce candesartan cilexetil.
U.S. Patent No. 5,196,444

US Patent No. 5,578,733 discloses deprotection of cilexetil trityl candesartan using a mineral acid under substantially anhydrous conditions.
U.S. Pat.No. 5,578,733

SUMMARY OF THE INVENTION One embodiment of the present invention is a method for preparing cilexetil trityl candesartan comprising reacting trityl candesartan, halogenated cilexetil, and at least one base in a low boiling organic solvent. A method comprising producing trityl candesartan; and isolating cilexetil trityl candesartan. The method further includes adding at least one phase transfer catalyst.

  In a preferred embodiment of the invention, the low boiling organic solvent in the process for preparing cilexetil trityl candesartan has a boiling point of less than about 140 EC.

  A method of preparing cilexetil candesartan comprises preparing cilexetil trityl candesartan comprising reacting trityl candesartan, halogenated cilexetil, and at least one base in a low boiling organic solvent to produce cilexetil trityl candesartan. Process.

  Another embodiment of the present invention provides cilexetil trityl candesartan; reacting cilexetil trityl candesartan with at least one organic solvent to produce cilexetil candesartan in at least one organic solvent; and It includes a method for synthesizing cilexetil candesartan comprising isolating cilexetil candesartan.

  One embodiment of the invention includes providing cilexetil trityl candesartan; mixing cilexetil trityl candesartan in the presence of acid free methanol; and isolating crude cilexetil candesartan. Includes synthesis of cilexetil candesartan.

  Another embodiment of the invention includes crystallizing crude candesartan cilexetil using a solvent system having at least two solvents; and recrystallizing crystalline candesartan cilexetil.

DETAILED DESCRIPTION OF THE INVENTION One embodiment of the present invention includes a method for the synthesis of cilexetil trityl candesartan from the reaction of trityl candesartan and cilexetil halide in the presence of a base and a low boiling organic solvent. Optionally, the reaction is performed in the presence of a phase transfer catalyst. Preferably the cilexetil halide is cilexetil chloride. Another embodiment of the present invention is the use of at least one organic acid optionally in the presence of a substantially anhydrous organic solvent to deprotect cilexetil trityl candesartan to produce cilexetil. Includes methods of making candesartan. Another embodiment of the invention includes a method of deprotecting cilexetil trityl candesartan to cilexetil candesartan using at least one inorganic acid in the presence of an aqueous solvent. Another embodiment of the invention includes a method of deprotecting cilexetil trityl candesartan to cilexetil candesartan in the presence of acid free methanol. Optionally, the method may further comprise crystallization and recrystallization of cilexetil candesartan.

  Typically, a method for synthesizing cilexetil trityl candesartan comprises reacting trityl candesartan, a halogenated cilexetil, and at least one base in a low-boiling organic solvent for a sufficient time and at a sufficient temperature, Including isolating candesartan. Preferably the cilexetil halide is cilexetil chloride. This method advantageously uses a low boiling organic solvent that is easy to remove from the product mixture and is environmentally safer than the solvents conventionally used in this synthesis. While not intending to be bound by theory, in some of the processes of the present invention, the base is insoluble in low boiling organic solvents and a two-phase system can be formed. Since the reaction takes place at the two-phase interface, the rate of such interfacial reactions is greatly increased by the use of a phase transfer catalyst (PTC).

  The solvent used in this method is a solvent having a low boiling point. Typically, the low boiling organic solvent has a boiling point of less than about 140EC, and preferably has a boiling point of less than about 120EC. Alternatively, the low boiling organic solvent is a pharmaceutically acceptable low boiling organic solvent having a boiling point of about 140EC to about 70EC, and preferably has a boiling point of about 120EC to about 80EC. Typically, the solvent includes, but is not limited to, at least one of a hydrocarbon aliphatic solvent, an aromatic solvent, or an ether. In a preferred embodiment, one solvent is acetonitrile (which has a boiling point of 81EC-82EC) or toluene (which has a boiling point of 110EC). In contrast, solvents used in the prior art (eg dimethylformamide) have a boiling point of 153EC. However, if DMF is used in the reaction of the present invention, the reaction temperature is about 50EC to about 55EC, not the reflux temperature.

  The base in the reaction may be at least one of an inorganic base or an organic base. The inorganic base used in the reaction is not particularly limited, but lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, Examples include potassium hydrogen carbonate and silver carbonate. The organic base used in the reaction is not particularly limited, but triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methyl-morpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo- [4.3.0 ] -5-Nene (DBN), 1,8-diazabicyclo- [5.4.0] unde-7-cene (DBU), or 1,4-diazabicyclo- [2.2.2] octane (DABCO). Preferably the base is potassium carbonate.

  Several classes of compounds are known that can act as phase transfer catalysts, such as quaternary ammonium compounds and phosphonium compounds, for example, only two. Phase transfer catalysts include, but are not limited to, tetrabutylammonium bromide, TEBA, tetrabutylammonium hydrogen sulfate, tricaprylmethylammonium chloride, benzyltriethylammonium chloride, cetyltrimethylammonium bromide, cetylpyridinium bromide, N-benzyl chloride Quinium, tetra-n-butylammonium chloride, tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride , Tetramethylammonium chloride, hexadecyltrimethylammonium chloride, or octyltrimethylammonium chloride. Preferably the phase transfer catalyst includes, but is not limited to, tetrabutylammonium bromide, TEBA, tricaprylmethylammonium chloride or tetrabutylammonium hydrogensulfate. Phase transfer catalysts are commercially available or can be readily synthesized by those skilled in the art. For example, tricaprylmethyl ammonium chloride (commonly known as Aliquat® 336) is manufactured by Aldrich Chemical Co. (Milwaukee, Wis.).

  The low boiling organic solvent used in the reaction allows a lower reaction temperature for the synthesis of cilexetil trityl candesartan. Based on low boiling solvents. Typically, the reaction temperature is from about 25EC to about 110EC, preferably from about 40EC to about 90EC. The reaction time depends on the amount of reactants, the reaction temperature, and other variables known to those skilled in the art.

  Another embodiment of the present invention is to deprotect cilexetil trityl candesartan (I) using a mixture of at least one organic solvent and at least one organic acid to produce crude cilexetil candesartan (II) To include a method. In another embodiment, the organic solvent may be a substantially anhydrous organic solvent. In yet another embodiment, the method includes a mineral acid in addition to the organic acid. Another embodiment of the present invention involves neutralizing excess acid in the reaction mixture with at least one base after adding the organic solvent. While not intending to be bound by theory, it is believed that organic acids are easily removed from the reaction mixture during normal processing. Thus, in general, organic acids are easier to use on an industrial scale. The present invention deprotects cilexetil trityl candesartan using an organic solvent with at least one organic acid. As used herein, the term “substantially anhydrous organic solvent” means an organic solvent having less than about 3 wt% water and preferably less than about 0.5 wt% water.

  The method is deprotection of cilexetil trityl candesartan: cilexetil trityl candesartan mixed with at least one organic acid in at least one organic solvent for a sufficient time and at a sufficient temperature. Synthesizes cetyl candesartan; and includes deprotection comprising isolating the crude cilexetil candesartan. This deprotection step is shown in Scheme I.

Organic acids contemplated by the methods of the present invention include, but are not limited to, at least one C ₆ -C ₁₀ aromatic sulfonic acid, haloacetic acid, C ₁ -C ₆ alkyl sulfonic acid, or C ₁ -C ₆ carboxylic acid There is. Preferably, the organic acid includes, but is not limited to, at least one methanesulfonic acid, formic acid, pyridine p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, or acetic acid. Preferably when using an organic acid, the reaction temperature may be from about 15EC to about 60EC. The reaction time can be readily determined by following the progress and / or completion of the reaction with thin layer chromatography (TLC). Typical reaction times are about 4 hours to about 20 hours.

Organic solvents include but are not limited to at least one alcohol, ketone, ether, hydrocarbon, or chlorinated solvent. Preferably the organic solvent is at least one C ₁ -C ₄ alkyl alcohol, ketone, ether, or chlorinated solvent. In particular, the organic solvent includes, but is not limited to, dichloromethane, methanol, toluene, and tert-butyl methyl ether. In certain embodiments where more than one solvent is used, the ratio of the first solvent to the second solvent is from about 1:10 to about 10: 1.

  After the trityl group is removed, the reaction mixture is neutralized using a base. Bases include those described above, and preferably the base is NaOH. Isolation of cilexetil candesartan is accomplished by extraction, evaporation, crystallization, or other common methods for isolating the desired organic compound from the reaction mixture. In a preferred embodiment, the solvent is distilled off under reduced pressure, then the residue is diluted with water and extracted with a suitable organic solvent (eg ethyl acetate). The organic extracts are combined, dried and the solvent is removed to give crude compound II.

  One embodiment of the present invention is deprotection of cilexetil trityl candesartan comprising: mixing cilexetil trityl candesartan without acid in the presence of methanol; and isolating cilexetil candesartan Includes deprotection. The deprotection step of the trityl group may be performed in the presence of water. In order to promote precipitation of the compound at the end of the reaction, the deprotection step of the trityl group may be performed in the presence of an organic solvent. This deprotection method gives a relatively clear product.

  Typically, the deprotection step involves heating to reflux trityl candesartan cilexetil in methanol. Optionally, the deprotection solvent mixture further comprises an organic solvent (eg, toluene) and / or an acid (eg, formic acid). Silexetil trityl candesartan is heated to reflux until a clear solution is obtained. Typically, the reaction temperature is about 30EC to about 90EC, preferably about 50EC to about 90EC, and the heating is performed for about 5 to about 19 hours, preferably about 8 hours to about 12 hours. The solvent is then distilled off to yield crude deprotected candesartan cilexetil. The solvent is removed at a temperature of about 30EC to about 70EC, preferably at a temperature of about 50EC and a reduced pressure of about 30 mbar.

  As used herein, the term “crude” refers to the product obtained from the deprotection reaction. Crude candesartan cilexetil is in solid or oily form.

  Typically, crude candesartan cilexetil is dissolved in a minimum amount of solvent system, and then the solution is slowly cooled until a crystalline candesartan cilexetil precipitate appears. Crystallization is induced by seeding, etching, cooling, or other common methods known to those skilled in the art. Optionally, the solution may be stirred during the crystallization process. Next, the crystalline candesartan cilexetil obtained in the first crystallization is dried. The drying step may be performed by heating crystalline candesartan cilexetil, optionally under reduced pressure, until a constant weight is obtained. Typically drying is performed at a temperature of about 45EC to about 65EC, preferably about 50EC to about 60EC. The decompression, when performed, includes about 30 mbar, although not particularly limited.

The solvent system includes at least two solvents, where one solvent is an alcohol and the other solvent is an aromatic compound. Typically, the alcohol is at least one C ₁ -C ₆ alcohol, including but not limited to methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, 1-pentanol, 2-pentanol Or 3-pentanol. Preferably the alcohol is methanol. The aromatic compound is at least one compound having a phenyl ring, and examples thereof include substituted or unsubstituted benzene, toluene, ethyltoluene, xylene, and mesitylene. Preferably the aromatic compound is toluene. Generally, the solvent system comprises alcohol and aromatics in a ratio of about 20% alcohol to 80% by weight aromatics, preferably the ratio of alcohol to aromatics is about 10% alcohol to 90% by weight aromatics. A solvent mixture of compounds. More preferably, the weight ratio of alcohol to aromatic compound is about 5% by weight alcohol to 95% by weight aromatic compound.

Recrystallization of crystalline candesartan cilexetil involves dissolving crystalline candesartan cilexetil in a solvent and recrystallizing to obtain substantially pure candesartan cilexetil. Optionally, this solution may be stirred during recrystallization. Typically the solvent is at least one C ₁ -C ₆ alcohol (but is not limited to methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, 1-pentanol, 2-pentanol, or Containing 3-pentanol). Preferably, the alcohol is methanol.

  Optionally, the method further comprises a drying step, wherein after the second recrystallization, the substantially pure candesartan cilexetil is dried at a suitable temperature and for a suitable time to obtain a substantially pure, constant weight. Fresh candesartan cilexetil is obtained. In general, the drying temperature is sufficient to remove undesirable solvents until the weight of crystalline candesartan cilexetil does not fluctuate. For example, the drying temperature is about 50EC to 65EC, preferably the drying temperature is about 50EC. Optionally, the drying step is performed under reduced pressure (including but not limited to about 8 mbar).

  Although the invention has been described with reference to several preferred embodiments, other embodiments will be apparent to those skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples detailing the preparation and deprotection methods of the compositions of the invention. It will be apparent to those skilled in the art that many modifications, both in materials and methods, are possible without departing from the spirit of the invention.

Example
Example 1: Preparation of cilexetil trityl candesartan in a low boiling point solvent Trityl candesartan (2.0 g, 2.93 mmol), cilexetil chloride (1.21 g, 5,86 mmol), potassium carbonate (0.81 g, 5.86 mmol) and acetonitrile ( 19 g) of the suspension was stirred at 40EC for about 8 hours and the reaction was followed by TLC. Acetonitrile was removed under reduced pressure (10 mbar) at 30EC-35EC and the residue was mixed with water (20 ml) and ethyl acetate (30 ml). The aqueous layer was separated and extracted with ethyl acetate (20 ml × 2). The combined organic layers were washed with brine (10 ml × 2), dried over sodium sulfate, and the solvent was evaporated to give crude cilexetil trityl candesartan as a semi-solid (HPLC purity 94.83%).

  The crude product was triturated with hexane (30 ml) at 25EC-27EC for 3 hours. The solid was then filtered off and the filter was washed with hexane (5 g x 2), dried under reduced pressure (10 mbar) at 25EC-27EC, and cilexetil trityl candesartan (12g, 84.8%) (by HPLC 94.64% purity) was obtained.

Example 2: Preparation of cilexetil trityl candesartan using PTC Trityl candesartan (2.0 g, 2.93 mmol), cilexetil chloride (1.21 g, 5,86 mmol), potassium carbonate (1.22 g, 8.83 mmol) in toluene (20 ml) ) And tetrabutylammonium hydrogensulfate (0.2 g) was stirred at 50EC-55EC for about 8.5 hours. The progress of the reaction was followed by TLC. The mixture was poured into water (100 ml) and neutralized with citric acid (solid). The organic layer was separated, washed with water and extracted with ethyl acetate (20 ml × 3). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, and the solvent was distilled off. The residue was triturated with hexane (20 ml) at 20-25 ° C. for about 30 minutes, filtered and dried at 40 ° C. to below about 30 mbar to give a white powder (1.68 g, 67.2%) (HPLC purity 97.90%). Obtained.

Example 3: Deprotection using methanesulfonic acid A solution of cilexetil trityl candesartan (0.50 g, 0.59 mmol), methanesulfonic acid (0.09 g, 0.88 mmol), dichloromethane (10 ml) and methanol (1 ml) Stir at ~ 27EC for about 4 hours. The reaction was followed using thin layer chromatography (TLC tracking). The reaction mixture was neutralized with saturated sodium bicarbonate solution and dichloromethane was removed under reduced pressure. The residue was diluted with water (10 ml) and extracted with ethyl acetate (20 ml × 2). The combined organic layers were washed with brine (10 ml × 2), dried over sodium sulfate, and the solvent was distilled off to obtain crude candesartan cilexetil.

Example 4: Deprotection method using p-toluenesulfonic acid cilexetil trityl candesartan (0.50 g, 0.59 mmol), PPTS (pyridine para-toluenesulfonic acid, 0.22 g, 0.88 mmol), dichloromethane (10 ml) and methanol ( 1 ml) was stirred at 25EC-27EC for about 20 hours. The progress of the reaction was followed using thin layer chromatography (TLC tracking). The reaction mixture was neutralized with saturated sodium bicarbonate solution. Dichloromethane was removed under reduced pressure, and the residue was diluted with water (10 ml) and extracted with ethyl acetate (20 ml × 2). The combined organic layers were washed with brine (10 ml × 2), dried over sodium sulfate, and the solvent was distilled off to obtain crude candesartan cilexetil.

Example 5: Deprotection method using formic acid A solution of cilexetil trityl candesartan (2.0 g, 2.35 mmol), formic acid (2.16 g, 46.9 mmol), dichloromethane (8 ml) and methanol (4 ml) at about 25EC-27EC Stir for 5 hours (TLC chase). The reaction mixture was neutralized with saturated sodium bicarbonate solution. Dichloromethane was removed under reduced pressure, and the residue was diluted with water (10 ml) and extracted with ethyl acetate (20 ml × 2). The combined organic layer was washed with brine (10 ml × 2), dried over sodium sulfate and evaporated to give an oil (2.05 g) which was tert-butyl methyl ether (TBME) (2.7 g). ) To give candesartan cilexetil (0.95 g, 66.4%).

Example 6: Deprotection using formic acid A solution of cilexetil trityl candesartan (1.0 g, 1.18 mmol) was dissolved in toluene (10 ml) at 50 EC to 55 EC, then formic acid (1.1 g, 23.88 mmol) and methanol (6 ml) was added. The solution was heated to 50EC-55EC for about 7 hours. The reaction mixture was cooled to 20EC-25EC, adjusted to pH 6.4 with 1N NaOH and extracted with ethyl acetate (20 ml × 3). The combined organic layers were washed with brine (10 ml × 2), dried over sodium sulfate, and the solvent was distilled off to obtain a semi-solid mass (0.79 g).

Example 7: Deprotection using formic acid A solution of trityl candesartan cilexetil (30 g, 0.035 mol) in toluene (180 ml), methanol (180 ml), and formic acid (1.6 g, 0.035 mol) in about 10 hours Refluxed over. The reaction was followed by HPLC. The solvent was then distilled off under reduced pressure (30 mbar) at a temperature of about 55EC to 60EC to reduce the solution volume to give a viscous oil (36.5 g). The oil was dissolved in a mixture of toluene: methanol (65.7 g: 7.3 g), stirred at about 0EC-5EC until crystallization started and maintained at 2EC-8EC for about 20 hours. The solid was collected by filtration and the filter was washed with a mixture of toluene / methanol (90:10 w / w, 15 g), dried under reduced pressure (10-50 mmHg) at a temperature of about 50 EC-55 EC, and then candesartan siloxane. Cetyl (16.88 g, 78.6%) was obtained as a white powder.

Example 8: Deprotection using trifluoroacetic acid The protecting group (trityl) was removed using a strong organic acid. To a stirred suspension of cilexetil trityl candesartan in methanol (6 ml) and toluene (6 ml), trifluoroacetic acid (0.1 ml, 1.3 eq) was added at 20EC-25 ° C. After stirring at 20EC-25 ° C for 50 minutes, a solution formed. The solution was further stirred at 20EC-25 ° C for about 6 hours. The pH of the solution was then adjusted to 6.4 with saturated aqueous sodium bicarbonate solution, the solution was diluted with brine (20 ml) and extracted with ethyl acetate (20 ml × 2). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered and evaporated to reduce the volume to give a semi-solid mass of crude candesartan cilexetil.

  Alternatively, trichloroacetic acid may be used in this manner.

Example 9: Deprotection using trifluoroacetic acid To a stirred suspension of cilexetil trityl candesartan (2g, 2.34mmol) in toluene (12ml) and methanol (12ml) was added trifluoroacetic acid (0.17g, 0.65). Equivalent) was added dropwise at about 20EC to about 25 ° C. A solution was formed after 1.5 hours of stirring and the solution was stirred at a temperature of about 20EC to about 25 ° C for an additional about 20 hours. The pH of the solution was then adjusted to pH 6.5 with saturated aqueous sodium bicarbonate solution, diluted with water (30 ml) and extracted with ethyl acetate (20 ml × 4). The organic layer was collected, dried over sodium sulfate, filtered and evaporated to give a semi-solid crude candesartan cilexetil.

Example 10: Deprotected cilexetil trityl candesartan (5.0 g, 5.86 mmol) without acid was dissolved in toluene (30 ml) at 60 ° C. Methanol (30 ml) was added and the solution was heated to 70 ° C. in an oil bath for about 19 hours. The volume of the solution was reduced to a weight of about 16 g under reduced pressure at 50EC-60 ° C. and then cooled at −10 ° C. for about 48 hours. The precipitated solid was collected by filtration, washed with cold methanol (methanol at about 0EC-5 ° C; 2 ml x 2), dried on the filter for about 1 hour and crude candesartan cilexetil (3.1 g, 88.5% ) The crude candesartan cilexetil was refluxed and dissolved in methanol (23 ml), the solution was filtered under reduced pressure and cooled in an ice bath with stirring for about 3 hours. The white solid was collected by filtration, washed with methanol (2.5 ml x 3), and dried overnight outdoors to give candesartan cilexetil as a white solid (2.3 g, 74%) (99.28% purity by HPLC) Obtained.

Example 11: Deprotection cilexetil trityl candesartan (20 g, 23 mmol) without acid was dissolved in toluene (120 ml) at 60EC. Methanol (120 ml) was added and the solution was heated in an oil bath at about 75EC-80EC for about 13 hours. Evaporate the solvent under reduced pressure at 50EC-60EC to reduce the volume of the solution to obtain a viscous residue (about 27g), dissolve it in methanol (60ml), evaporate the solvent to dryness and foam A product (about 23 g) was obtained. This foam was dissolved in methanol (about 40 g) at reflux temperature. The solution was then filtered under reduced pressure and cooled to 4EC to give a solid that was maintained at this temperature for 12-15 hours.

  The precipitated solid was collected by filtration, washed with cold methanol (20 ml × 2) at about 0EC-5 ° C. and dried under vacuum at 50 ° C. to give candesartan cilexetil (15.5 g). Candesartan cilexetil (1 g) was pulverized with toluene (5 ml) at 25EC to 27EC for 1 hour to obtain candesartan cilexetil (about 0.65 g).

Example 12: Deprotected trityl candesartan cilexetil (20 g, 23.45 mmol) without acid A mixture of toluene (60 ml), methanol (60 ml) and water (1 ml) was gently refluxed for about 12 hours. The reaction was followed by HPLC. The solvent was distilled off under reduced pressure (30 mbar) at a temperature of about 55EC-60EC to reduce the volume of the solution to give a viscous oil of candesartan cilexetil as a residue (36.5g).

Example 13: Deprotected trityl candesartan cilexetil without acid (20 g, 23.45 mmol), toluene (60 ml), methanol (60 ml) and water (1 ml) were gently refluxed for about 5 hours. The progress of the reaction was followed by HPLC. The solvent was distilled off under reduced pressure (30 mbar) at a temperature of about 55EC-60EC to reduce the volume of the solution to give a viscous oil of candesartan cilexetil as a residue (36.5g).

Example 14: A deprotected trityl candesartan cilexetil (20 g, 23.45 mmol), methanol (200 ml) and water (1 ml) mixture without acid was gently refluxed for about 16-17 hours. The progress of the reaction was followed by HPLC. The solvent was distilled off under reduced pressure (30 mbar) at a temperature of 55EC-60EC to reduce the volume of the solution to give a viscous oil of candesartan cilexetil as a residue.

Example 15: A solution of deprotected trityl candesartan c (TCS, 350 g, 410.3 mmol), toluene (1050 ml), methanol (2100 ml) and water (17.0 ml) without acid is refluxed for about 2-4 hours. (HPLC control), evaporation of the solvent at 40-50 ° C./P<100 mbar to give a residue as a viscous oil, the residue at 45-55 ° C. in a toluene / methanol mixture (1041 g, 95: 5, A clear solution was obtained by dissolving in the w / w) mixture.

  The solution is cooled to (-5) to (20) ° C., the solution is maintained at this temperature for about 8-12 hours, the precipitated solid is filtered off and washed on the filter with cold toluene (350 ml) To obtain a wet solid (295.8 g, 83%). 110 g of wet solid was dried at 50 ° C./10 mbar for 2-6 hours to give a wet white solid (94 g (LOD = 15-25%)). Wet white solid (43.75 g) is dissolved in absolute ethanol (215-363 ml 6-10 V) at 40-60 ° C., the solution is filtered and returned to the reaction vessel, then the solution is (-15)-(5) Cooled to 0 C and maintained at this temperature for about 2-24 hours. The precipitated solid was removed by filtration and washed with cold absolute ethanol (23-35 ml) to give a wet solid, which was dried at 50 ° C./10 mbar until constant weight to give cilexetil candesartan. (21.5g, 67%).

Example 16: Deprotection of deprotected cilexetil trityl candesartan without acid (50.0 g, 58.62 mmol), water (2.64 g, 2.5 eq), and methanol (500 ml, 10 eq volume) in about 16.5 hours The solution was refluxed to obtain a clear solution. The solvent was distilled off at 30 mbar and 40 EC to give a solid residue (51.7 g). The residue was dissolved at 60EC in a mixture of toluene / methanol (95: 5 w / w, 125 g), cooled to 20-23EC and stirred for about 15 hours. A precipitate appeared and was collected by filtration, washed with a cold (4 ° C.) mixture of toluene / methanol (95: 5 w / w, 25 g), dried at 50 EC and 30 mbar for 2 hours, and crude. Solid candesartan cilexetil (32.41 g, 90.5%) (99.32% purity by HPLC) was obtained.

Example 17: Deprotected cilexetil trityl candesartan (100.0 g, 0.117 mol), water (5.3 g), toluene (600 ml) and methanol (600 ml) without acid are refluxed for about 10 hours (process control) And the solvent was distilled off at 60 ° C./30 mbar to obtain an oily residue. Part of the residue (6.84 g) was dissolved in a mixture of toluene / methanol (95: 5 w / w, 11.2 g) at 50 ° C. The solution is stirred at 2-8 ° C. for about 6 hours, the solid is filtered off, washed with a cold mixture of toluene / methanol (95: 5 w / w, 3.4 g), dried at 60 EC / 30 mbar and white A solid (3.47 g, 86.8%) (99.15% purity by HPLC) was obtained.

Example 18: Recrystallization with methanol The compound of Example 8 (5 g) is dissolved in methanol (25.0 g) at about 18EC-23 ° C. to obtain a clear solution, and a solid precipitates to form a suspension. did. The suspension was stirred at 18EC-23EC for about 60 hours and the resulting solid was collected by filtration, washed with methanol (2.5 g), and solid at a temperature of about 50EC-55EC under reduced pressure (10 mbar). Was dried until a constant weight was obtained to give candesartan cilexetil (4.2 g, 84%) as a white powder.

Example 19: Recrystallization from methanol The compound of Example 8 (2g) was dissolved in methanol (6.0g) at 50EC to obtain a clear solution. The solution was cooled at about 18EC-23EC until a precipitate began to form. The suspension is then stirred at 18EC-23EC for about 60 hours, and the solid is collected by filtration, washed with methanol (1.0 g), and solids at a temperature of about 50EC-55EC under reduced pressure (10 mbar). Drying to a constant weight gave candesartan cilexetil (1.74 g, 87.0%) as a white powder.

Example 20: Recrystallization from ethanol The compound of Example 8 (5 g) was dissolved in ethanol (25.0 g) at 50EC to obtain a clear solution. The solution was cooled at about 18EC-23EC until a precipitate began to form. The suspension is stirred at 18EC-23EC for about 60 hours, the solid is collected by filtration, washed with ethanol (2.5 g), and a constant weight of solid at a temperature of about 50EC-55EC under reduced pressure (10 mbar) To obtain candesartan cilexetil (4.17 g, 83.4%) as a white powder.

Example 21: Recrystallization from ethanol The compound of Example 1 (2g) was dissolved in ethanol (25.0g) at 60EC to obtain a clear solution. The solution was cooled at about 18EC-23EC until a precipitate began to form. The suspension is stirred at 18EC-23EC for about 60 hours, the solid is collected by filtration, washed with ethanol (1.0 g), and the solid remains constant at a temperature of about 50EC-55EC under reduced pressure (10 mbar). Drying to weight gave candesartan cilexetil (1.68 g, 84.0%) as a white powder.

Claims (61)

A method for preparing cilexetil trityl candesartan comprising:
Reacting trityl candesartan, halogenated cilexetil, and at least one base in a low boiling organic solvent to produce cilexetil trityl candesartan; and isolating cilexetil trityl candesartan;
A method involving that.   The process according to claim 1, wherein the reaction is carried out in the presence of a phase transfer catalyst.   2. The method of claim 1, wherein the cilexetil halide is cilexetil chloride.   The method of claim 1, wherein the low boiling organic solvent has a boiling point of less than about 140 EC.   5. The method of claim 4, wherein the low boiling organic solvent has a boiling point less than about 120EC.   2. The method according to claim 1, wherein the low boiling point organic solvent is at least one of an aliphatic solvent, an aromatic solvent, or an ether.   The process according to claim 1, wherein the low-boiling organic solvent is acetonitrile or toluene.   2. The method of claim 1, wherein the low boiling organic solvent is a pharmaceutically acceptable low boiling organic solvent having a boiling point of about 140EC to about 70EC.   9. The method of claim 8, wherein the low boiling organic solvent is a pharmaceutically acceptable low boiling organic solvent having a boiling point of about 120EC to about 80.   2. The method of claim 1, wherein the base is selected from the group consisting of inorganic bases.   The base is at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, or silver carbonate. 11. The method of claim 10, wherein   2. The method of claim 1, wherein the base is selected from the group consisting of organic bases.   The base is triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methyl-morpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo- [4.3.0] no-5-ene (DBN), 13. The method of claim 12, wherein the method is at least one of 1,8-diazabicyclo- [5.4.0] unde-7-cene (DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO).   The phase transfer catalyst is tetrabutylammonium bromide, TEBA, tetrabutylammonium hydrogen sulfate, tricaprylmethylammonium chloride, benzyltriethylammonium chloride, cetyltrimethylammonium bromide, cetylpyridinium bromide, N-benzylquininium chloride, Tetra-n-butylammonium hydroxide, tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, tetramethyl chloride 3. The method of claim 2, wherein the method is at least one of ammonium, hexadecyltrimethylammonium chloride, or octyltrimethylammonium chloride.   3. The method of claim 2, wherein the phase transfer catalyst is at least one of tetrabutylammonium bromide, TEBA, tricaprylmethylammonium chloride, or tetrabutylammonium hydrogensulfate.   2. The method of claim 1, wherein the method is performed at a temperature of about 25EC to about 110EC.   17. The method of claim 16, wherein the method is performed at a temperature of about 40EC to about 90EC.   The process according to any one of claims 1 to 17, in a method for preparing candesartan cilexetil. A method for the synthesis of cilexetil candesartan comprising:
Reacting cilexetil trityl candesartan with at least one organic acid to produce cilexetil candesartan in at least one organic solvent; and isolating the crude cilexetil candesartan;
A method involving that.   20. The method of claim 19, further comprising neutralizing excess acid in the reaction mixture with at least one base prior to isolating the crude cilexetil candesartan.   20. The method of claim 19, further comprising adding a mineral acid.   20. The method of claim 19, wherein the organic acid is selected from the group consisting of methanesulfonic acid, formic acid, pyridine p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, or acetic acid.   20. The method of claim 19, wherein the method is performed at a reaction temperature of about 15EC to about 60EC.   The method of claim 19, wherein the organic solvent is substantially anhydrous.   25. The method of claim 24, wherein the substantially anhydrous organic solvent has less than about 3% water by weight.   26. The method of claim 25, wherein the substantially anhydrous organic solvent has less than about 0.5 wt% water. Wherein the substantially organic anhydrous solvent is a C ₁ -C ₄ alkyl alcohols, ketones, ethers, hydrocarbons or chlorinated solvents, The method of claim 19.   28. The method of claim 27, wherein the substantially anhydrous organic solvent is dichloromethane, methanol, toluene, or tert-butyl methyl ether.   20. The method of claim 19, wherein more than one solvent is used.   30. The method of claim 29, wherein the ratio of the first solvent to the second solvent is from about 1:10 to about 10: 1.   The base is triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methyl-morpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo- [4.3.0] no-5-ene (DBN), 21. The at least one of 1,8-diazabicyclo- [5.4.0] unde-7-cene (DBU), 1,4-diazabicyclo- [2.2.2] octane (DABCO) or NaOH. Method.   32. The method of claim 31, wherein the base is NaOH. A method for the synthesis of cilexetil candesartan comprising:
Reacting cilexetil trityl candesartan with methanol to produce cilexetil candesartan; and isolating the crude cilexetil candesartan;
A method involving that.   34. A method according to claim 33, wherein the reaction takes place without acid.   A method of synthesizing cilexetil candesartan without acid, comprising deprotecting cilexetil trityl candesartan to produce cilexetil candesartan.   36. The method of claim 35, further comprising crystallizing the cilexetil candesartan.   34. The method of claim 33, further comprising adding at least one organic solvent.   34. The method of claim 33, further comprising adding water.   34. The method of claim 33, wherein the method is performed at a reaction temperature of about 30EC to about 90EC.   40. The method of claim 39, wherein the method is conducted at a reaction temperature of about 50EC to about 90EC.   The method according to any one of claims 19 and 33, wherein the cilexetil trityl candesartan is produced by the method according to any one of claims 1 to 17.   34. The method of any one of claims 19 or 33, further comprising crystallizing the crude candesartan cilexetil in a solvent system to obtain crystalline candesartan cilexetil. The solvent system is C ₁ -C ₆ alcohols and aromatics The method of claim 42. The C ₁ -C ₆ alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, 1-pentanol, 2-pentanol, and 3-pentanol; 44. The method of claim 43. Wherein C ₁ -C ₆ alcohol is methanol The method of claim 44.   44. The method of claim 43, wherein the aromatic compound is selected from the group consisting of benzene, toluene, ethyltoluene, xylene, or mesitylene.   48. The method of claim 46, wherein the aromatic compound is toluene. Wherein the ratio of C ₁ -C ₆ alcohol to aromatic compound is about 20 wt% to about 80 wt%, The method of claim 43. Wherein the ratio of C ₁ -C ₆ alcohol to aromatic compound is about 10 wt% to about 90 wt%, The method of claim 48. Wherein the ratio of C ₁ -C ₆ alcohol to aromatic compound is about 5 wt% to about 95 wt%, The method of claim 49.   44. The method of claim 43, further comprising recrystallizing crystalline candesartan cilexetil in a solvent to obtain substantially pure candesartan cilexetil. Wherein the solvent is C ₁ -C ₆ alcohol, The method of claim 51. The C ₁ -C ₆ alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, 1-pentanol, 2-pentanol, and 3-pentanol; 53. The method of claim 52.   52. The method of claim 51, further comprising drying pure candesartan cilexetil. A process for preparing cilexetil trityl candesartan comprising:
Reacting trityl candesartan, halogenated cilexetil and DMF at a temperature of about 50EC to about 55EC to produce cilexetil trityl candesartan; and isolating cilexetil trityl candesartan;
A method involving that.   56. The method of claim 55, wherein the reaction is performed in the presence of a phase transfer catalyst.   56. The method of claim 55, wherein the cilexetil halide is cilexetil chloride.   56. The method of claim 55, wherein the base is selected from the group consisting of inorganic bases.   56. The method of claim 55, wherein the base is selected from the group consisting of organic bases. A process for preparing cilexetil trityl candesartan comprising:
Mixing trityl candesartan, cilexetil chloride, and potassium carbonate in acetonitrile;
Heating the reaction to the reflux temperature of acetonitrile to produce cilexetil trityl candesartan; and isolating cilexetil trityl candesartan;
A method involving that.   61. The method of claim 60, wherein the reactant is heated to 40EC for about 8 hours.